Journal
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Volume 25, Issue 12, Pages 1891-1899Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1440-1746.2010.06312.x
Keywords
antioxidant; Bax; Bcl-2; bucillamine; F-2 isoprostane; glutathione; ischemia-reperfusion injury; liver
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Background and Aim: Liver transplantation and resection surgery involve a period of ischemia and reperfusion to the liver, which initiates an inflammatory cascade resulting in liver and remote organ injury. Bucillamine is a low molecular weight thiol antioxidant that is capable of rapidly entering cells. We hypothesized that bucillamine acts by replenishing glutathione levels, thus reducing neutrophil activation, modulating Bax/Bcl-2 expression, and subsequently, attenuating the effects of warm ischemia-reperfusion injury (IRI) in the liver. Methods: The effect of bucillamine was studied in a rat model of liver IRI with 45 min of partial (70%) liver ischemia and 3 h of reperfusion. Liver injury was assessed by measuring serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and liver histology. Oxidative stress was quantified by measuring F-2 isoprostane and glutathione levels. Leukocyte adhesion was assessed by intravital microscopy, and inflammatory cytokine response was assessed by measuring serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels. Bax and Bcl-2 expression was measured by reverse transcription-polymerase chain reaction. Results: The model produced significant liver injury with elevated transaminases and an acute inflammatory response. Bucillamine reduced the liver injury, as indicated by reduced AST (932 +/- 200.8 vs 2072.5 +/- 511.79, P < 0.05). Bucillamine reduced Bax expression, serum CINC-1 levels, and neutrophil adhesion, and upregulated Bcl-2. However, bucillamine did not affect tissue glutathione levels nor the levels of oxidative stress, as measured by plasma and hepatic F-2 isoprostane levels. Conclusions: Bucillamine reduces warm ischemia-reperfusion in the liver by inhibiting neutrophil activation and modulating Bax/Bcl-2 expression.
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